2. Academic Validation
  3. Alternative splicing and residual function potentially expand the therapeutic landscape of the CFTRdele2ins182 variant

Alternative splicing and residual function potentially expand the therapeutic landscape of the CFTRdele2ins182 variant

  • PLoS One. 2025 Sep 16;20(9):e0330974. doi: 10.1371/journal.pone.0330974.
Cristina Pastorino 1,  Ludovica Menta 2,  Emanuela Pesce 1 2,  Mariateresa Lena 2,  Valeria Tomati 1,  Valeria Capurro 1,  Marco Di Duca 1,  Vito Terlizzi 3,  Andrea Gramegna 4 5,  Francesco Blasi 4 5,  Carlo Castellani 6,  Serena Cappato 1,  Federico Zara 1 2,  Nicoletta Pedemonte 1,  Renata Bocciardi 1 2
Affiliations

Affiliations

  • 1 Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
  • 2 Department of Neurosciences, rehabilitation, Ophthalmology; Genetics and Maternal and Child Sciences (DINOGMI), University of Genoa, Genoa, Italy.
  • 3 Department of Pediatric Medicine, Meyer Children's Hospital IRCCS, Cystic Fibrosis Regional Reference Centre, Florence, Italy.
  • 4 Respiratory Unit and Cystic Fibrosis Adult Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
  • 5 Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
  • 6 Cystic Fibrosis Center, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
PMID: 40956828 DOI: 10.1371/journal.pone.0330974
Abstract

This study investigates the molecular and functional consequences of rare CFTR variants, particularly focusing on the complex allele [186-13C > G; 1898 + 3A > G] and the CFTRdele2ins182 rearrangement. Using patient-derived nasal epithelial cells, the research characterized the transcripts produced by these variants, revealing that CFTRdele2ins182, previously considered a null allele, generates alternative mRNA isoforms, one of which potentially encodes a partially functional CFTR protein. Functional assays in both heterologous and patient-derived cell models explored the impact of CFTR modulators on these variant proteins. While some rescue of CFTR activity was observed with specific modulator combinations in certain variants, the study highlights the complexity of genotype-phenotype correlations in CF and emphasizes the importance of personalized functional characterization of rare CFTR variants to guide therapeutic strategies. The findings suggest that even variants thought to be null alleles may produce proteins with residual function, opening avenues for developing targeted therapies for a broader range of CF patients.

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